Design of Biomolecular Therapeutics
Protein and nucleic acid drugs demonstrate great promise as molecular therapeutics, but design of their properties for enhanced efficacy and reduced toxicity needs to be better informed by quantitative principles developed from quantitative models for their interactions within the greater cell, tissue, and systemic behavioral context. We are combining molecular-level design with higher-level modeling to try to develop improved protein and nucleic acid drugs; specific applications currently include GCSF, IL-2, Fc-fusion protein conjugates, and synthetic and viral vectors for gene therapeutics.
(BE postdoctoral) in collaboration with Prof. Dane Wittrup (BE/ChE, MIT) and Prof. Steve Wiley (PNL) Quantitative investigations of the most common mutation of the EGF receptor, EGFRvIII. Studies include both experimental and computational approaches to determining trafficking, signaling, and cellular responses under a range of EGFRvIII expression levels and the effects of antibody based therapeutics on altering those behaviors.
(ChE doctoral), in collaboration with Prof. Linda Griffith (ME/BE / BEH, MIT) and Prof. Jack Wands (Brown Univ. Medical School)
BPEC: Gene delivery to hepatic capillaries beds in tissue-engineered liver microarrays, in comparison to standard cell culture. The objective is to develop an improved in vitro methodology for studying barriers to in vivo gene delivery, including extracellular transport and cellular uptake.
Experimental and computational analysis of therapeutic strategies targeting the ErbB receptor family. Measurements of EGF- and HRG-mediated signaling and trafficking in the presence of three classes of ErbB-targeted therapeutics are used in the development of a model for predicting therapeutic effect for different ErbB expression profiles.
BPEC: Quantitative studies of replication-deficient adenoviral vector effects on intracellular signaling dynamics and cell apoptotic response to the cytokine TNF-alpha. Application towards improving recombinant Ad gene therapy, especially cancer therapy.
(BE doctoral), in collaboration with Prof. Linda Griffith (BE/ME, MIT)
BPEC: Non-viral gene delivery studies in primary liver cells and tissue-engineered liver bioreactors. Quantitative studies of vector/plasmid trafficking and expression of gene payload for the development of a mathematical model describing gene delivery in a three-dimensional tissue construct. Further analysis and optimization of model parameters could provide insight for increased non-viral transfection efficiency and development of novel polymer carriers.